My laboratory is interested in the organization and expression of genes at the end of the long arm of the human X chromosome and their relationship to human disease. We have cloned and characterized a cDNA for the human HPRT gene, and we now plan to characterize the genomic structure of the HPRT gene to determine the nature of the genetic defects in the Lesch-Nyhan syndrome and in gouty arthritis associated with partial HPRT deficiency. We shall characterize flanking sequences by "chromosome walking" methods, using either lambda genomic clones or the larger cosmid genomic clones already available in our laboratory. Furthermore, we will study the organization of human sequences present in a series of hamster-human hybrid cells known to contain the human HPRT gene together with variable amounts of sequences extending in both directions along the human X chromosome. We also plan to use a variety of other X-linked genes, including those for G6PD, factor VIIIc, and regions associated with fragile X, color blindness and other markers to be mapped to this region. By these methods and by nucleotide sequence determination, we hope to determine the organization of the large portion of the human X chromosome extending from near the HPRT transcription insert to the end of the long arm of the chromosome, and to correlate mutations in this region with a variety of disorders.